Modern robot-assisted radiosurgery of cerebral angiomas-own experiences, system comparisons, and comprehensive literature overview.

Cerebral arteriovenous malformations (AVMs) are rare vascular lesions potentially responsible for substantial neurological morbidity and mortality. Over the past four decades, radiosurgery has become a valid therapeutic option for many patients with small intracranial AVMs, but reports describing the use of robotic stereotactic radiosurgery (SRS) are rare. The purposes of this study are to describe the efficacy and toxicity of robotic SRS for AVMs and to review the literature. The reports of 48 consecutive patients treated with SRS were reviewed. A total dose of 18 Gy in a single fraction was prescribed to the 70% isodose line. Efficacy (i.e., total obliteration of the AVM) and toxicity were analyzed. Literature search was performed on Embase and PubMed for the terms "Radiosurgery and AVMs", "Cyberknife and AVMs" and "Radiation therapy and AVMs." The median follow-up was 41 months. The median AVM volume was 2.62 cm3. The incidence of obliteration was 59% at 3 years. Regarding toxicity, 92% of patients remained symptom-free, 66% developed radiogenic edema on MRI, and none developed radionecrosis. Forty-one patients (85%) had embolization prior to SRS. Our study was incorporated in an exhaustive review of 25 trials categorized by SRS technique. In this review, the median follow-up was 60 months. The median nidus volume was 2 cm3. The median overall obliteration rate for SRS was 68% (range 36 to 92). The median embolization rate prior to SRS was 31% (range 8.23 to 90). Compared to other studies, tolerability was excellent and the obliteration rate was acceptable but probably affected by the high embolization rate prior to radiosurgery. Our study suggests that a higher dose is feasible. A larger cohort with a longer follow-up period will be needed to confirm the safety and effectiveness, and subsequently validate different prognosis and predictive scores with this treatment modality to maximize the benefits of this technology for selected patients in the long term.

[Place of Linacs in extracranial stereotactic radiotherapy: Are they now equivalent to Cyberknife®?] / Place des Linacs dans la radiothérapie stéréotaxique extra crânienne : sont-ils désormais non inférieurs au Cyberknife® ?

Extracranial stereotactic radiotherapy has developed recently, since the years 1990-2000. Devices specifically dedicated to this type of treatment were then developed and shared the favors of radiation oncologists: Tomotherapy® and especially Cyberknife®, which offered the advantage of "tracking" with the possibility of real time motion correction, allowing an increase in the precision of targeting volumes. Recently, the latest generations of linear accelerators (Linac) have been developed, integrating much higher dose rates, an improved ballistic precision with a very short treatment duration time and the possibility of real time motion management (with notably the possibility of adaptive radiotherapy in real time with the development of "MLC tracking"). So are Linacs able to perform equivalent (not inferior) extracranial stereotactic radiotherapy treatments to those with Cyberknife®, the historical gold standard in this field? This article presents a comparison of these two treatment devices, by successively considering dose distributions in the irradiated volume, distant received doses from this volume (including the "integral dose"), problems linked to the duration of the sessions and those linked to motion management.

Use Of Area-Based Socioeconomic Deprivation Indices: A Scoping Review And Qualitative Analysis.

There is considerable interest among researchers, clinicians, and policy makers in understanding the impact of place on health. In this scoping review and qualitative analysis, we sought to assess area-level socioeconomic deprivation indices used in public health and health outcomes research in the US. We conducted a systematic scoping review to identify area-level socioeconomic deprivation indices commonly used in the US since 2015. We then qualitatively compared the indices based on the input-variable domains, data sources, index creation characteristics, index accessibility, the geography over which the index is applied, and the nature of the output measure or measures. We identified fifteen commonly used indices of area-level socioeconomic deprivation. There were notable differences in the characteristics of each index, particularly in how they define socioeconomic deprivation based on input-variable domains, the geography over which they are applied, and their output measures. These characteristics can help guide future index selection and application in clinical care, research, and policy decisions.

Hydrogen sulfide donor protects against mechanical ventilation-induced atrophy and contractile dysfunction in the rat diaphragm.

Mechanical ventilation (MV) is a clinical tool providing adequate alveolar ventilation in patients that require respiratory support. Although a life-saving intervention for critically ill patients, prolonged MV results in the rapid development of inspiratory muscle weakness due to both diaphragmatic atrophy and contractile dysfunction; collectively known as "ventilator-induced diaphragm dysfunction" (VIDD). VIDD is a severe clinical problem because diaphragmatic weakness is a risk factor for difficulties in weaning patients from MV. Currently, no standard treatment to prevent VIDD exists. Nonetheless, growing evidence reveals that hydrogen sulfide (H2 S) possesses cytoprotective properties capable of protecting skeletal muscles against several hallmarks of VIDD, including oxidative damage, accelerated proteolysis, and mitochondrial damage. Therefore, we used an established animal model of MV to test the hypothesis that treatment with sodium sulfide (H2 S donor) will defend against VIDD. Our results confirm that sodium sulfide was sufficient to protect the diaphragm against both MV-induced fiber atrophy and contractile dysfunction. H2 S prevents MV-induced damage to diaphragmatic mitochondria as evidenced by protection against mitochondrial uncoupling. Moreover, treatment with sodium sulfide prevented the MV-induced activation of the proteases, calpain, and caspase-3 in the diaphragm. Taken together, these results support the hypothesis that treatment with a H2 S donor protects the diaphragm against VIDD. These outcomes provide the first evidence that H2 S has therapeutic potential to protect against MV-induced diaphragm weakness and to reduce difficulties in weaning patients from the ventilator. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Mechanical ventilation (MV) results in diaphragm atrophy and contractile dysfunction, known as ventilator-induced diaphragm dysfunction (VIDD). VIDD is important because diaphragm weakness is a risk factor for problems in weaning patients from MV. Currently, no accepted treatment exists to protect against VIDD. Growing evidence reveals that hydrogen sulfide (H2 S) donors protect skeletal muscle against ischemia-reperfusion-induced injury. Nonetheless, it is unknown if treatment with a H2 S donor can protect against VIDD. WHAT QUESTION DID THIS STUDY ADDRESS? Can treatment with an H2 S donor protect against VIDD? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study provides the first evidence that treatment with a H2 S donor protects against VIDD. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These new findings provide the basis for further exploration of H2 S donors as a therapy to prevent VIDD and reduce the risk of problems in weaning patients from MV.

Modification of Neuromuscular Junction Protein Expression by Exercise and Doxorubicin.

PURPOSE: Doxorubicin (DOX) is a highly effective antitumor agent widely used in cancer treatment. However, it is well established that DOX induces muscular atrophy and impairs force production. Although no therapeutic interventions exist to combat DOX-induced muscle weakness, endurance exercise training has been shown to reduce skeletal muscle damage caused by DOX administration. Numerous studies have attempted to identify molecular mechanisms responsible for exercise-induced protection against DOX myotoxicity. Nevertheless, the mechanisms by which endurance exercise protects against DOX-induced muscle weakness remain elusive. In this regard, impairments to the neuromuscular junction (NMJ) are associated with muscle wasting, and studies indicate that physical exercise can rescue NMJ fragmentation. Therefore, we tested the hypothesis that exercise protects against DOX-induced myopathy by preventing detrimental changes to key proteins responsible for maintenance of the NMJ. METHODS: Female Sprague-Dawley rats were assigned to sedentary or exercise-trained groups. Exercise training consisted of a 5-d treadmill habituation period followed by 10 d of running (60 min·d, 30 m·min, 0% grade). After the last training bout, exercise-trained and sedentary animals were paired with either placebo (saline) or DOX (20 mg·kg i.p.) treatment. Two days after drug treatment, the soleus muscle was excised for subsequent analyses. RESULTS: Our results indicate that endurance exercise training prevents soleus muscle atrophy and contractile dysfunction in DOX-treated animals. These adaptations were associated with the increased expression of the following neurotrophic factors: brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, nerve growth factor, and neurotrophin-3. In addition, exercise enhanced the expression of receptor-associated protein of the synapse and the acetylcholine receptor (AChR) subunits AChRß, AChRδ, and AChRγ in DOX-treated animals. CONCLUSION: Therefore, upregulating neurotrophic factor and NMJ protein expression may be an effective strategy to prevent DOX-induced skeletal muscle dysfunction.

Radiotherapy in Patients With a Cardiac Implantable Electronic Device.

Recently, the Heart Rhythm Society published recommendations on management of patients with cardiac implantable electronic device (CIED) who require radiotherapy (RT). We aimed to report the experience of a teaching hospital, and discuss our practice in the context of recently published guidelines. We identified all consecutive CIED recipients (12,736 patients) who underwent RT between March 2006 and June 2017. Among them, 90 (1%) patients (78.2 ± 10 years, 73% male) had a CIED: 82 pacemakers and 8 implantable cardioverter-defibrillators. Two patients required CIED extraction prior to RT for ipsilateral breast cancer (no device replacement in 1 patient). Four patients (5%) were considered at high-risk, 35 (39%) at intermediate-risk, and the remaining 50 (56%) at low-risk for CIED dysfunction. Overall, only a minority of patients followed recommended local protocol during RT delivery (31%) and during follow-up (56%). CIED malfunction was detected in 5 patients (6%), mainly back-up mode resetting (80%), with 4 (including 3 pelvic cancer location) patients initially classified as being at intermediate-risk and 1 at low-risk. Four out of the 5 patients with CEID malfunction had received neutron producing beams. In conclusion, our findings underline the lack of rigorous monitoring of patients undergoing RT (though CIED malfunction appears to be rare and relatively benign in nature), and emphasize the interest of considering neutron producing beam for risk stratification as recommended in recent guidelines. Optimization of patient's management requires a close collaboration between both CIED clinicians and radiation oncologists, and more systematic remote CIED monitoring may be helpful.

Mitochondrial accumulation of doxorubicin in cardiac and diaphragm muscle following exercise preconditioning.

Doxorubicin (DOX) is a highly effective anthracycline antibiotic. Unfortunately, the clinical use of DOX is limited by the risk of deleterious effects to cardiac and respiratory (i.e. diaphragm) muscle, resulting from mitochondrial reactive oxygen species (ROS) production. In this regard, exercise is demonstrated to protect against DOX-induced myotoxicity and prevent mitochondrial dysfunction. However, the protective mechanisms are currently unclear. We hypothesized that exercise may induce protection by increasing the expression of mitochondria-specific ATP-binding cassette (ABC) transporters and reducing mitochondrial DOX accumulation. Our results confirm this finding and demonstrate that two weeks of exercise preconditioning is sufficient to prevent cardiorespiratory dysfunction.

Exercise Training Prevents Doxorubicin-induced Mitochondrial Dysfunction of the Liver.

PURPOSE: Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of a broad spectrum of cancers. However, clinical use of DOX is limited by irreversible and dose-dependent hepatotoxicity. The liver is the primary organ responsible for the clearance of antineoplastic agents, and evidence indicates that hepatotoxicity occurs as a result of impaired mitochondrial efficiency during DOX metabolism. In this regard, exercise training is sufficient to improve mitochondrial function and protect against DOX-induced cytotoxicity. Therefore, the purpose of this study was to determine whether short-term exercise preconditioning is sufficient to protect against DOX-induced liver mitochondrionopathy. METHODS: Female Sprague-Dawley rats (4-6 months old) were randomly assigned to one of four groups: 1) sedentary, treated with saline; 2) sedentary, treated with DOX; 3) exercise trained, treated with saline; and 4) exercise trained, treated with DOX. Exercise-trained animals underwent 5 d of treadmill running habituation followed by 10 d of running for 60 min·d (30 m·min; 0% grade). After the last training bout, exercise-trained and sedentary animals were injected with either DOX (20 mg·kg i.p.) or saline. Two days after drug treatment, the liver was removed and mitochondria were isolated. RESULTS: DOX treatment induced mitochondrial dysfunction of the liver in sedentary animals because of alterations in mitochondrial oxidative capacity, biogenesis, degradation, and protein acetylation. Furthermore, exercise preconditioning protected against DOX-mediated liver mitochondrionopathy, which was associated with the maintenance of mitochondrial oxidative capacity and protein acetylation. CONCLUSION: These findings demonstrate that endurance exercise training protects against DOX-induced liver mitochondrial dysfunction, which was attributed to modifications in organelle oxidative capacity and mitochondrial protein acetylation.

Tumor burden and location as prognostic factors in patients treated by iodine seed implant brachytherapy for localized prostate cancers.

BACKGROUND: Iodine seed implant brachytherapy is indicated for low risk and selected favorable intermediate risk prostate cancers. A percentage of positive biopsies > 50% is usually considered as a contra-indication, and the tumor location could also influence the treatment efficacy. We studied the association of the percentage of positive biopsy cores, and tumor location, with progression-free survival. METHODS: Among the 382 patients treated at our center by permanent implant iodine seed brachytherapy for a localized prostate cancer between 2006 and 2013, 282 had accessible detailed pathology reports, a minimum follow-up of 6 months, and were included. Progression was defined as a biochemical, local, nodal, or distant metastatic relapse. We studied cancer location on biopsies (base, midgland or apex of the prostate) and percentage of positive biopsy cores, as well as potential confounders (pre-treatment PSA, tumor stage, Gleason score, risk group according to D'Amico's classification modified by Zumsteg, adjunction of androgen deprivation therapy, and dosimetric data). RESULTS: Most patients (197; 69.9%) had a low risk, 67 (23.8%) a favorable intermediate risk, 16 (5.7%) an unfavorable intermediate risk, and 1 (0.3%) a high-risk prostate cancer. An involvement of the apex was found for 131 patients (46,5%), of the midgland for 149 (52,8%), and of the base for 145 (51,4%). The median percentage of positive biopsy cores was 17% [3-75%]. The median follow-up was 64 months [12-140]. Twenty patients (7%) progressed: 4 progressions (20%) were biochemical only, 7 (35%) were prostatic or seminal, 6 (30%) were nodal, and 3 (15%) were metastatic. The median time to failure was 39.5 months [9-108]. There were more Gleason scores ≥7 among patients who progressed (40% vs 19%; p = 0.042). None of the studied covariates (including tumor location, and percentage of positive biopsy cores), were significantly associated with progression-free survival. The risk group showed a trend towards an association (p = 0.055). CONCLUSIONS: Brachytherapy is an efficient treatment (5-year control rate of 93%) for patients carefully selected with classical criteria. The percentage and location of positive biopsies were not significantly associated with progression-free survival. A Gleason score ≥ 7 was more frequent in case of progression.

Increased SOD2 in the diaphragm contributes to exercise-induced protection against ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in rapid diaphragmatic atrophy and contractile dysfunction, collectively termed ventilator-induced diaphragm dysfunction (VIDD). Recent evidence reveals that endurance exercise training, performed prior to MV, protects the diaphragm against VIDD. While the mechanism(s) responsible for this exercise-induced protection against VIDD remain unknown, increased diaphragm antioxidant expression may be required. To investigate the role that increased antioxidants play in this protection, we tested the hypothesis that elevated levels of the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) is required to achieve exercise-induced protection against VIDD. Cause and effect was investigated in two ways. First, we prevented the exercise-induced increase in diaphragmatic SOD2 via delivery of an antisense oligonucleotide targeted against SOD2 post-exercise. Second, using transgene overexpression of SOD2, we determined the effects of increased SOD2 in the diaphragm independent of exercise training. Results from these experiments revealed that prevention of the exercise-induced increases in diaphragmatic SOD2 results in a loss of exercise-mediated protection against MV-induced diaphragm atrophy and a partial loss of protection against MV-induced diaphragmatic contractile dysfunction. In contrast, transgenic overexpression of SOD2 in the diaphragm, independent of exercise, did not protect against MV-induced diaphragmatic atrophy and provided only partial protection against MV-induced diaphragmatic contractile dysfunction. Collectively, these results demonstrate that increased diaphragmatic levels of SOD2 are essential to achieve the full benefit of exercise-induced protection against VIDD.

Image-guided adaptive brachytherapy in primary vaginal cancers: A monocentric experience.

PURPOSE: Primary vaginal cancer is a rare disease for which treatment has been modeled based on cervical cancer. We report our experience in the use of image-guided adaptive brachytherapy (IGABT) in this indication. METHODS AND MATERIALS: Patients treated for vaginal cancer with a combination of external beam radiation therapy and IGABT were identified through electronic search. The Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology recommendations for cervical cancer have been extrapolated with the definition of two clinical target volumes (CTVs) corresponding to the residual disease after external beam radiation therapy (CTVBT), assessed from clinical and imaging findings, and the so-called CTVi, comprising the CTVBT with directional margins and at least the initial disease at diagnosis. RESULTS: Twenty-seven patients were identified. MRI was used for brachytherapy guidance in 82% of the cases. An interstitial component was used in 59% of the cases. The D90 CTVBT and D90 CTVi were 73.1 ± 12.8 Gy and 66.6 ± 6.7 Gy, respectively. After a median followup of 40.1 months, nine recurrences in 8 patients were observed of which four were local. Local relapses occurred within the CTVBT. Three-year local control and disease-free rates were 82% and 65%, respectively. At 2 years, the Grade 2-4 gastrointestinal or urinary morbidity accrual rate was 9%. Twelve patients experienced late sexual morbidity, including three patients with Grade 3 stenosis. CONCLUSION: IGABT is feasible in vaginal cancer with promising outcomes. Harmonizing the definition of CTVs is required to allow comparisons between experiences and to perform multicenter studies.

Tumor response assessment by MRI following stereotactic body radiation therapy for hepatocellular carcinoma.

BACKGROUND: To evaluate the MRI features of a tumor response, local control, and predictive factors of local control after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). METHODS: Thirty-five consecutive patients with 48 HCCs who were treated by SBRT were included in this retrospective study. All patients provided written informed consent to be treated by SBRT, and prior to inclusion they authorized use of the treatment data for further studies. The assessment was made using MRI, with determination of local and hepatic responses according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria during a two-year follow-up. RESULTS: The local response rate according to mRECIST was higher than with RECIST. A tumor diameter less than 20 mm at baseline was an independent predictive factor for RECIST and mRECIST responses, as was diffusion-weighted signal for RECIST. During follow-up, a tumor diameter of <20 mm (p = 0.034) and absence of a high intensity on T2-weighted (p = 0.006) and diffusion-weighted images (p = 0.039) were associated with a better response according to RECIST. Post-treatment changes include peritumoral ring-like enhanced changes with high intensity on T2-weighted images. CONCLUSIONS: SBRT is a promising technique for the treatment of inoperable HCC. Post-treatment changes on MRI images can resemble tumor progression and as such must be adequately distinguished. The regression of tumorous enhancement is variable over time, although diffusion-weighted and T2-weighted intensities are predictive factors for tumor RECIST responses on subsequent MRIs. They hence provide a way to reliably predict treatment responses.

Effect of bladder distension on doses to organs at risk in Pulsed-Dose-Rate 3D image-guided adaptive brachytherapy for locally advanced cervical cancer.

PURPOSE: To evaluate the impact of bladder distension on doses to organs at risk in patients treated with 3D image-guided adaptive pulsed-dose-rate (PDR) brachytherapy (BT) for locally advanced cervical cancer. METHODS AND MATERIALS: Twenty-two patients who had previously been treated by external beam radiation therapy (EBRT), underwent BT treatment planning to a pelvic MRI (or a CT scan in case of contraindication) after their bladder was filled with 100 cc of physiological saline (full bladder). This was immediately followed by a CT scan after emptying of the bladder. A fusion of these two examinations was conducted, and the dosimetry was duplicated for the study with an empty bladder. Equieffective doses of 2 Gy per fraction from EBRT and BT of bladder/rectum/sigmoid colon/small bowel were compared. RESULTS: A full bladder condition was found to be non-inferior in terms of the bladder D2cc (a difference of -0.9 Gy; 97.5% CI [-∞; 2.6]), and it resulted in a reduction in the bladder D0.1cc (p = 0.038). Bladder expansion resulted in a significant reduction of maximum doses received by the small bowel, both in terms of the D0.1cc (51.2 Gy vs. 63.4 Gy, p < 0.001) and the D2cc (48.5 Gy vs. 53.6 Gy, p < 0.001). A negative correlation was seen between the difference in the small bowel D2cc and the body mass index; (r = -0.55; p = 0.008). No differences were noted in regard to doses to the rectum and sigmoid colon. CONCLUSIONS: Bladder distension with 100 cc of physiological saline can reduce maximum doses received by the small bowel without the alteration of the doses received by the other organs at risk during a 3D image-guided adaptive PDR BT for locally advanced cervical cancer. However, the maintenance of a predefined bladder volume is difficult to achieve with PDR BT, whereas it could be easily managed before each session in case of high-dose-rate BT.

Contribution of image-guided adaptive brachytherapy to pelvic nodes treatment in locally advanced cervical cancer.

PURPOSE: With the increasing use of simultaneous integrated boost in the treatment of cervical cancer, there is a need to anticipate the brachytherapy (BT) contribution at the level of the pathologic pelvic lymph nodes. This study aimed to report the dose delivered at their level during BT. METHODS AND MATERIALS: Patients with pelvic nodal involvement and treated with a combination of chemoradiation followed by image-guided adaptive pulsed-dose-rate BT were selected. On per BT three-dimensional images, pelvic lymphadenopathies were delineated, without planning aim. For the purposes of the study, D100, D98, D90, and D50 were reviewed and converted in 2-Gy equivalent doses, using the linear quadratic model with an α/ß of 10 Gy. RESULTS: Ninety-one patients were identified, allowing evaluation at the level of 226 lymphadenopathies. The majority of them were external iliac (48%), followed by common iliac (25%), and internal iliac (16%) regions. The 2-Gy equivalent doses D98 were 4.4 ± 1.9 Gy, 5.4 ± 3.1 Gy, and 4.3 ± 2.1 Gy for the obturator, internal iliac, and external iliac, respectively, and 2.8 ± 2.5 Gy for the common iliac. The contribution to the common iliac nodes was significantly lower than the one of external and internal iliac (p < 0.001). CONCLUSIONS: BT significantly contributes to the treatment of pelvic nodes at the level of approximately 5 Gy in the internal, external, and obturator areas and 2.5 Gy in the common iliac, allowing the anticipation of nodal boost with the simultaneous integrated boost technique. However, important individual variations have been observed, and evaluation of the genuine BT contribution should be recommended.

Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma.

PURPOSE: To describe efficacy and safety of stereotactic body radiation therapy (SBRT) for the treatment of inoperable hepatocellular carcinoma. METHODS: The records of 77 consecutive patients treated with SBRT for 97 liver-confined HCC were reviewed. A total dose of 45Gy in 3 fractions was prescribed to the 80% isodose line. Local control (LC), overall survival (OS), progression-free survival (PFS) and toxicity were studied. RESULTS: The median follow-up was 12months. The median tumor diameter was 2.4cm. The LC rate was 99% at 1 and 2years. The 1 and 2-year OS were 81.8% and 56.6% respectively. The median time to progression was 9months (0-38). The rate of hepatic toxicity was 7.7% [1.6-13.7], 14.9% [5.7-23.2] and 23.1% [9.9-34.3] at 6months, 1year and 2years respectively. In multivariate analysis, female gender (HR 7.87 [3.14-19.69]), a BCLC B-C stage (HR 3.71 [1.41-9.76]), a sum of all lesion diameters ⩾2cm (HR 7.48 [2.09-26.83]) and a previous treatment (HR 0.10 [0.01-0.79]) were independent prognostic factors of overall survival. CONCLUSION: SBRT allows high local control for inoperable hepatocellular carcinomas. It should be considered when an ablative treatment is indicated in Child A patients.